6-acyl-xanthone-2-carboxylic acids

ABSTRACT

Compositions containing and methods employing, as the essential ingredient, novel substituted xanthone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions and intermediates therein are also disclosed. 6-Acetyl-xanthone-2-carboxylic acid is illustrated as a representative compound.

United States Patent [191 Pfister et al.

6-ACYL-XANTHONE-2-CARBOXYLIC ACIDS Inventors: Jurg R. Pfister, Los Altos; Ian T. Harrison; John H. Fried, both of Appl. No.: 259,671

Related US. Application Data Continuation-impart of Ser. No. 231,756, March 3, 1972.

US. Cl. 260/335, 424/283 Int. Cl C07d 7/44 Field of Search 260/335 June 28, 1974 [56] References Cited UNITED STATES PATENTS 3,706,768 12/1972 Bays 260/335 Primary Examiner-Norma S. Milestone Attorney, Agent, or Firm-Evelyn K. Merker; Walter H. Dreger [5 7 ABSTRACT Compositions containing and methods employing, as the essential ingredient, novel substituted xanthone carboxylic acid compounds which are useful in the treatment of allergic conditions. Methods for preparing these compounds and compositions and intermediates therein are also disclosed. 6-Acetyl-xanthone-2- carboxylic acid is illustrated as a representative compound.

4 Claims, No Drawings asiq mpsmssqtt s fqrm lai 1 6-ACYL-XANTHONE-2-CARBOXYLIC ACIDS andthe pharmaceutically acceptable, non-toxic esters,

amides and salts thereof; wherein R is a group selected fr9mth9s of h formulas (wherein R is hydrogen, loweralkyl, cycloalkyl, tetrahydrofuran-2-yl, tetrahydrdpyran-Z-yl, tetrahydropy- ,3-

ran-4-yl,- 4-alkoxytetrahydropyran-4-yl, or carboxylic' acyl containing up to 12 carbon atoms, and each of R and R is hydrogen; lower alkyl; cycloalkyl; phenyl, substituted phenyl, in' which the substituent is halo,

' lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl, or cyano; or a monocyclic aromatic heterocyclic group having five or six total members, one or two of which are selected from nitrogen, oxygen, and sulfur); lower alkylsulfinyl; lower alkylsulfonyl; sulfo; sulfamoyl; monolower alkylsulfamoyl; or dilower alkylsulfamoyl.

Thus included within thescope of the present invention are (l) The C-6l-hydroxyalkyl substituted xanthone-Z-carboxylic acid compounds of the formula:

RIO COOH Reta 2. The'lC-6 acyl substituted xanthone-2j-carboxylic 3. The C6 lower alkylsult'myl substituted xanthone- 2 -:carboxy lic acid compounds-of the formula d 1 d 2 4. The C6 lower alkylsulfonyl substituted xanthoner o a d s mPP ss9f bs emale... 1

A COOH 0 hi) l) g 0.

5. The C-6 sulfo substituted xazithone-Z-carboxylic s j qis yoiisd Q thsi a i si t.

l 6. The C-6 sulfamoyl, N-monolower alkylsulfamoyl, I

and N,N-dilower alkylsulfamoyl substituted xanthone- .zxy qasid 9 9 999 19? 9?- lhf9fl11lfhi COOH 0 Rom-s \0 and the pharmaceutically acceptable, non-toxic esters, amides and salts thereof; wherein each of R, R and R is as above defined, R being preferably hydrogen,

methyl or acetyl, each of R and R is lower alkyl, and each of R is hydrogen, or lower alkyl.

In a second aspect, the present invention is directed to a method useful for relieving symtoms associated with allergic manifestations such as are brought about by antigen-antibody (allergic) reactions. In the relief of these systoms, the method hereof serves to inhibit'the effects of the allergic reaction when administered in an effective amount. While notintending to be bound by any theoretical mechanism of action, the method hereof is believed to operate by inhibiting the release and/or the action of toxic products, e.g., histamine, 5-hydroxytryptamine, slow releasing substance (SRS- A), and others, which are produced as a result of a combination of specific antibody and antigen (allergic reaction). These properties make the subject com pounds particularly useful in the treatment of various allergic conditions.

This aspect of the present invention thus relates to a method useful for inhibiting the effects of the allergic reaction which comprises administering an effective amount of a compound selected from those represented by the above formula (A) or a pharmaceutically acceptable non-toxic composition incorporating said acids, esters, amides or salts as an essential ingredient.

The present invention, in a third aspect, is directed to pharmaceutical compositions useful for inhibiting are therefore useful in the treatment of conditions in which such agents may be indicated, as for instance in the treatment of bronchio constriction. The compounds of the present invention are also vasodilators and are therefore useful in the treatment of conditions in which such agents may be indicated, as for instance in renal and cardiac disorders.

In the practice of the method of the present invention, an effective amount of a compound of the present invention or pharmaceutical compositions thereof, as defined above, is administered via any of the usual and acceptable methods known in the art, either singly or in combination with another compound or compounds of the present invention or other pharmaceutical agents, such as antibiotics, hormonal agents, and so forth. These compounds or compositions can thus be administered orally, topically, parenterally, or by inhalation and in the form of either solid, liquid, or gaseous dosages including tablets, suspensions, and aerosols, as discussed in more detail .hereinafter. The. administration can be conducted in single unit dosage form with continuous therapy or in single dose therapy ad libitum. In the preferred embodiments the method of the present-inven tion is practiced whenrelief of symptoms is specifically required, or, perhaps, imminent; however, the method hereof is also usefully practiced as continuous or prophylactic treatment.

In view of the foregoing as well as in consideration of the degree or severity of the condition being treated, age of subject, and so forth, all of which factors being determinable by routine experimentation by one skilled in the art; the effective dosage in accordance herewith can vary over a wide range. Generally, an effective amount ranged from about 0.005 to about 100 mg. per kg. of body weight per day and preferably from about 0.01 to about I00 mg per kg. of body weight per day.

I .0 Kl Q Q Q i 0 a s 7 01x 0 v 0 v 0 ln alternate terms, an effective amount in accordance herewith generally ranges from about 0.5 to about Useful pharmaceutical carriers for the preparation of the compositions hereof, can be solids, liquids, or gases. Thus, the compositions can take the form of tablets, pills, capsules, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, and the like. The carriers can be selected from the various oils including those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water, ethanol, and the like. Suitable pharmaceutical carriers and their formulation are described in Remingtons Pharmaceutical Sciences" by E. W. Martin. Such compositions will, in any event, contain an effective amount of the active compound together with a suitable amount of carrier so as to prepare the proper dosage form for proper administration to the host.

The compounds of the presentinvention demonstrate activity as inhibitors of the effects of the allergic reaction as measured by tests indicative of such activity involving passive cutaneous anaphylaxis as substantially described, for example, by J. Goose et al., Immunology, 16, 749 (1969).

Certain of the compounds of the present invention can be prepared in accordance with the following reaction sequence:

COOH

coon oooH i COR1 A COOR7 i HO 0/ (R m: 0 I \O HS (RB)NOS COOR7 0 000R n -s R4- i R -s R4- (Ig \0 (I; 0/ (D) (E) i A 00011 i CPL CO'OH A 000E i i HO- R N wherein ciiF'o'iR, R, and R is as above efined, aria each of R, R, and R is lower alkyl, R being preferably methyl.

With reference to the above reaction sequence, paramethyl phenol (2) is condensed with the 2,4-, dichlorobenzoic acid (1) in the presence of copper The reaction is preferably conducted in an inert organic reaction medium, such as those listed above, or suitable mixtures of one or more of such media. The reaction is further conducted at temperatures ranging from about to about 220C, preferably from about [20 to 200C, and for a period of time sufficient to complete the reaction, ranging from about 2 hours to about 24 hours.

The reaction consumes the reactants on thebasis of one mole of the substituted phenol per mole of the dichlorobenoic acid. However, the amount of the reactants to be employed are not critical, some-of the de-' sired compound (3) product being obtained when employing any proportions thereof. in the preferred embodiments, the reaction is conducted by reacting from about 1 to about 3 moles of the substituted phenol compound with about from 1 to about 1.2 moles of the dichlorobenzoic acid compound in the presence of catalytic amounts of the copper powder. The inert organic reaction medium, if employed, is used in solvent amounts.

Thereafter, the prepared compound (3) is oxidized with potassium permanganate in aqueous t-butanol to give the corresponding 2-(p-carboxyphenyloxy)-4- chlorobenzoic acid (4). g

The thus-prepared'diaeid compound (4) is then cyclized with phosphoryl chloride, thionyl chloride, sulfuric acid, hydrogen fluoride, or, preferably, polyphosphoric acid (PPA), to give the corresponding b-chloroxanthone-2-carboxylic acid compound (5). The reaction is preferably, but optionally, conducted in an inert organic reaction medium includingthose usually employed in organic chemical reactions, such as dimethylsulfoxide, sulfolane, benzene, toluene, and so forth. The reaction is further conducted at temperatures ranging from about 60 to about 180C, and for a period of time sufficient to complete the reaction ranging from about minutes to about 90 minutes.

Although the reaction consumes the reactants on the basis of one mole of compound (4) per mole of cyclizing reagent, the reaction can be performed using any proportions of reactants. 1n the preferred embodiments, however, the reaction is conducted using from about to about 50 moles of the cyclizing reagent per mole of starting compound 4).

The 6-chloroxanthone-2-carboxylic acid (5) is then treated with excess alkali metal lower alkoxide, e. g., sodium methoxide to give compound (7) or with excess alkali metal thioloweralkoxide to give compounds (6). The reaction is preferably conducted in polar organic solvent at temperatures of from about 80 to about 150C.

The 6-methoxyxanthone-2-carboxylic acid compound 7) thus prepared is converted to the respective 6-hydroxy compound by treatment with hydrobromic or hydroiodic acid and acetic acid. This reaction is conducted at a temperature of from about 100 to about 160C followed by esterification (R to give compounds (8). This reaction is conducted with ethereal diazoalkane such as diazomethane and diazoethane or with the desired lower alkyl iodide in thepresence of lithium carbonate at room temperature or with the desired lower alkanol in the presence of a trace of sulfuric acid at reflux.

The hydroxy acid esters (8) are then treated with a dialkylthiocarbamoyl chloride, such as dimethylthiocarbamoyl chloride, in the presence of base, such as an alkali metal hydride, and in organic liquid reaction media, preferably an organic amide such as those listed above with respect to reaction (1 2 3) to afford the products (9). The reaction is conducted at temperatures ranging from about 20 to about 100C, preferably from 60 to about 80C and for a period of time sufficient to complete the reaction, ranging from about 1 hour to about 6 hours. In the preferred embodiments,

' the reaction is conducted by reaction of from about 1.1

to about 1.5 moles of dialkylthiocarbamoyl chloride per mole of compound (8).

The product compounds (9) are then rearranged by reaction at a temperature of from about 200 to about 250C, preferably from about 220 to about 230C, and for a period of time ranging from about 1 hour to about 8 hours and in the presence of organic medium such as sulfolane, nitrobenzene, triethyleneglycol, and so forth, which is preferably employed in solvent amounts, to give compound 10).

Compounds (10) are then converted to the corresponding o-mercapto acid compounds 1 1 by base hydrolysis using an alkali metal hydroxide at about to about 90C and for a period of time sufficient to complete the reaction, ranging from about 15- minutes to about 60 minutes, preferably in the presence of inert organic reaction media such as those normally employed in organic chemical reactions of this type, eg aqueous alkanol solutions.

The 6-lower alkylthio ether, ester compounds can be prepared by reacting compounds (11) with a lower alkyl halide in the presence of base such as potassium carbonate and organic liquid reaction media such as those described above. The reaction is conducted at a temperature ranging from about 20 to about 80C, preferably from 50 to about 60C and for a period of time sufficient to complete the reaction, ranging from about 2 hours to about 16 hours- Hydrolysis of the ester, if desired, affords the 6-(lower alkylthioJ-acid com.- pounds (6).

Compound (6) is esterified to the .acid ester, or the acid ester thereof prepared as described above, can be oxidized with a peracid, such as peracetic acid, mchloroperbenzoic acid, p-nitroperbenzoic acid, perphthalic acid, and so forth, to give compounds 12) which can be hydrolyzed, as above described, to give-the corresponding 6-lower alkylsulfinyl acid compounds (D). The oxidation is preferably conducted in liquid reaction media such as a chlorinated hydrocarbon, e.g.

.chloroform, methylene chloride, and carbon tetrachloride. The reaction is conducted at temperatures ranging from about 0 to about 60C, preferably from 20 to about 30C and for a period of time sufficient to tion is conducted by reaction of from about 1 to about 1.l moles of peracid.

Alternatively, the acid esters of compounds (6) are oxidized with excess hydrogen peroxide to give compounds (l3which can be hydroylzed above described to give the 6-lower alkysulfonyl acid compounds (E). The peroxide oxidation is preferably conducted in liquid reaction media such as a lower carboxylic acid, e.g. acetic acid and propionic acid. The reaction is further conducted at'temperatures ranging from about 20 to about 100C, preferably from to about C and for a period of time sufficient to complete the reaction. ranging from about 30 minutes to about 3 hours. In the preferred embodiments, the reaction is conducted by reaction of from about 5 to about 10 moles of hydrogen peroxide per mole of the esters of compound (6).

In said oxidation steps. and particularly that employing peracid, a mixture of products (12) and (13) may be obtained. If obtained. the mixture can be conventionally separated, such as via chromatography, if desired, to isolatethe oxidized products.

The above oxidation steps can also be practicedon the acid starting compounds (6) to give respective products (D) or (E) without the need of. a second hydrolysis step.

Alternatively, compounds (1]) can be treated with excess chlorine under acidic conditions to afford compounds'( 14). This reaction is conducted employing a pH of about I by use of hydrochloric acid, optionally in acetic acid solution. The reaction is further conducted at temperatures ranging from about 20 to about 100C, preferably from 50 to about 60C and for a period of time sufficient to complete the reaction, ranging from about 2 hours to about 12 hours.

Compound (14) is then reacted with a base, such as alkali metal hydroxide, preferably under aqueous conditions and at a temperature ranging from about 20 to about 100C, preferably from 80 to about 90C and for a period of from about 1 hour to about 2 hours to give the 6-sulfo-substituted acid compounds (F).

Compounds (14) can be treated with ammonia, monolower alkylamine, or dilower alkylamine to give the 6-sulfamoyl, monolower alkylsulfamoyl, and dilower alkylsulfamoyl acid compounds (G). This reaction is conducted at temperatures ranging from about to about 80C, preferably from to about 30C, and for a period of time sufficient to complete the reaction, ranging from about 1 hour to about 8 hours. In the preferred embodiments, the reaction is conducted by V halo is bromo, chloro, fluoro, or iodo, preferably reaction of from about 10 to about 20 moles of amine per mole of compound (14). This reaction is further,

conducted in organic reaction media such as those described above, preferably tetrahydrofuran, dioxane, di-

methylsulfoxide, and so forth.

hal

. l0 ent invention can be prepared in accordance with the following:

Sequence B R OH v COOH wherein R is lower alkylthio, or chloro, R is as' defined above; and

then hydrolyzed (i.e. l0 11 in Sequence A) to give the diacid compounds (18) which are cyclized as described above to compounds (19). The products are useful as described and depicted by'Sequence A.

Certain compounds hereof are prepared as illustrated by the following sequence:

Sequence 0 cooH w en Ri -e11 O Y O RILOH O II OOH c0011 11 wherein R is lower alkyl; and each of R, R R and halo is as above defined.

With reference to the above reaction sequence, the

o-substituted-xanthone-2-carboxylic compounds (23) are prepared following the above reaction Sequence B 16 17 l8- l9)with the respective starting compounds (20). The resultant compounds (23 or their esters, are oxidized with chromium trioxide in acetic acid-acetic anhydride to give the 6-acyl compounds (C) which are'reduced with sodium borohydride to give the 6-(secondary hydroxyalkyl)- xanthone-Z-carboxylic acid products (D). Alternative to the above procedure, the 6-substituted xanthone-2- carboxylic acid (23) can be converted to its corresponding ester and it treated with N-bromosuccinimide to prepare the corresponding o-(substituted bromomethyl) compound (Le. I dill-Br) which can be converted to the corresponding alcohol upon treatment with aqueous base, to give the product acids (B).

Certain of thecompounds hereof can be prepared as follows:

wherein R is as defined above.

In the above Sequence, compounds (24) and-(l5) are condensed as described above, e.g. 1 2 3, to

give the diacid compound (25) which is cyclized as described above, e.g. 4 5, to give compound (7) which is useful as depicted and described in Sequence A above.

An alternative method for the preparation of certain of the compounds hereof is represented as follows:

Sequence E R QOH CH CH I ha] R COOH ooorr m l R9 RP boon ( 9) V V 7 (l8) 7 a This compound is then oxidized such as with potassium permanganate in aqueous t-butanol, as described above, e.g. 3 4, to give (18) which is then cyclized, as described above, to give the corresponding -zanthone-2-carboxylic acid (19) useful as described above to prepare the compounds of the present inventron.

Certain of the, compounds hereof in the 6 hydroxyalkyl and 6-acyl series can be prepared by treating acetanilide with an appropriate acid chloride, e.g. benzoyl chloride, to give the corresponding pacylacetanilide compound, converting the latter with dilute mineral acid to p-acylaniline. The latter is treated with bromine to give the corresponding 0- bromo-p-acylaniline which, when treated with sodium nitrite and sodium fluoroborate followed by treatment with nickel carbonyl, gives the corresponding o-bromop-acylbenzoic acid. The latter is esterified and reacted with p-hydroxybenzoate followed by hydrolysis and cyclization, all as described above, to give the o-acylxanthone-2-carboxylic acid compounds. Reduction of the acyl group, as described above, affords the corresponding 6-hydroxyalkyl compounds.

The carboxylic acyl esters of the hydroxy alkyl substituted compounds (i.e. R'=carboxylic acyl) are prepared as described above or by secondary alcohol esterification methods known per se. One such method involves treating the products represented by Formula (B) with a carboxylic acid chloride or carboxylic acid anhydride in the presence of a base, preferably pyridine, at temperatures ranging from about 60 to about C and for a period of time ranging from about one 13 by treatment of the xanthone acid ester with the appropriate alkylor cycloalkyl halide and sodium hydride in, e.g. dimethylformamide, followed by hydrolysis, as

described above. The etherification reaction is 'conducted at from about 50 to about 80C and for from about 1 to about hours.

reaction medium, e.g. benzene, at about room temper ature up to reflux, for from about two to about five days, followed by hydrolysis of the acid ester, as described above.

The 4-alkoxytetrahydropyran-4-yloxy ethers are prepared by treatment of the'alcohol with 4-alkoxy-5,6- dihydro-2H-pyran, as described above for the preparation of the furanyl and pyranyl ethers, followed by acid ester hydrolysis. Treatment of the 4-alkoxytetrahydropyran-4-yloxy ether with aluminum chloride and lithium aluminum hydride in organic reaction medium affords the corresponding tetrahydropyran-4-yloxy ethers which are'oxidized to give the corresponding ethers in the xanthone acid series. The latter can be directly prepared by treating the alcohol with 4-bromotetrahydropyran and base.

The acid esters of the 'xanthone-Z-car-boxylic acids hereof are prepared as described above upon treatment of the acid with ethereal diazoalkane such as diazomethane and diazoethane or with the desired lower alkyl iodide in the presence of lithiumcarbonate at room temperature or with the desired lower alkanol in the presence of a trace of sulfuric acid at reflux. The glycerol esters are prepared by treating the acid with thionyl chloride followed by treatment with a'suitably protected ethylene glycol or propylene glycol (e.g. solketal) in pyridine, and hydrolyzing the protecting group of the ester thus formed with dilute acid.

The amides of the xanthone-2carboxylic' acids hereof are prepared by treatment of the acids with thionyl chloride followed by treatment with anhydrous ammonia, alkyl amine, dialkyl amine, dialkylaminoalkylamine, alkoxyalkylamine, or phenethylamine.

The salts of the xanthone-Z-carboxylic acids hereof are prepared by treating the corresponding acids with a pharmaceutically acceptable base. Representative salts derived from such pharmaceuticallyacceptable bases include the sodium, potassium, lithium, ammo-v nia, calcium, magnesium, ferrous, ferric, zinc, manganous, aluminum, manganic, trimethylamine, triethylamine, tripropylamine, B-(dimethylamino)- ethanol, triethanolamine, B-(diethylamino)ethanol, arginine, lysine, histidine, N-ethylpiperidine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methyl I glucamine, theobromine, purines, piperazine, piperidine, polyamine resins, caffeine, procaine salts. The reaction is conducted in an aqueous solution, alone or in 100C, preferably at room temperature. Typical inert,

water-miscible organic solvents include methanol, ethanol, isopropanol, butanol, acetone, dioxane, or tetrahydrofuran. When divalent metal salts are prepared, such as the calcium salts or magnesium salts-of the acids, the free acid starting'material is treated with about one-half molar equivalent of pharmaceutically acceptable base. When the aluminum salts of the acids are prepared, about one-third molar equivalent of the pharmaceutically acceptable base is employed.

In the preferred embodiment of the present invention, the calcium salts and magnesium salts of the acids are prepared by treating the corresponding sodium or potassium salts of the acids with at least one-half molar equivalent of calcium chloride or magnesium chloride, respectively, in an aqueous solution, alone or in combination with an inert water-miscible organic solvent, at a temperature of from about 20C to about C.

In the preferred embodiment of the present invention, the aluminium salts of the acids are prepared by treating the acids with at least one-third molar equivalent of an aluminum alkoxide, such as aluminum triethoxide; aluminum tripropoxide, and the like, in a hydrocarbon solvent, such as benzene, xylene, cyclohexane, and the like, at a temperature of from 20C to about C.

In the sulfo series, use of one equivalent of base provides the sulfo acid monosalts; use of two equivalents provides the disalts.

The starting compounds for use in the present invention are known and can be prepared in accordance with known procedures. Thus, the l ,3- dicarbo(lower)alkoxy-4-halobenzene starting compounds are conveniently prepared by oxidizing l,3-dimethyl-4-halobenzene (4-halo-m-xylene) with potassium permanganate, as described above, followed by conventional esterification. Lower alkoxyphenylcarboxylic acid chloride acylating agents for the preparation of alkoxyphenylcarbonylacetanilide starting com-. pounds, are prepared, for example,'by selectively esterifying hydroitybenzoic acid with methanol and a trace of sulfuric acid or with lithium carbonate and methyl halide in dimethylformamide. The resultant hydroxybenzoate ester is then conventionally alkylated with lower alkylhalide and potassium carbonate followed by selective hydrolysis of the ester of the carboxylic acid group and conversion to the acid chloride with, e. g. thionyl chloride.

In the present specification and claims, by the term lower alkyl is intended a lower alkyl group containing one to eight carbon atoms including straight and branched chain groups, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, sec-butyl', t-butyl,

n-pentyl, isopentyLsec-pentyl, t-pentyl, n-hexyl, n-

pentyl, n-octyl, isooctyl. The term 'cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, and cycloalkylor glycerol ester; an unsubstituted, monoalkyl, di-

alkyl, dialkylaminoalkyl, alkoxyalkyl, or phenethyl sub- -clo[2.2.2]octane-l-carboxylate, adamantoate, dihydrogen phosphate, dib enzyl phosphate, sodium ethyl phosphate, sodium sulfate, sulfate, and the like.

In the hydroxyalkyl and alkylsulfinyl series the compounds may possess a chiral center. The methods hereof generate each of the d and l and d1 forms and each is thus included within the scope hereof. If desired, the isomers can be separated by conventional means such as forming thealkaloid salts of th'products and employing fractional crystallization.

The nomenclature herein is employed in accordance with Chemical Abstracts, 56, Subject Index 1962', January June).

The following examples illustrate the method by which the present invention can-be practiced.

Example 1 A mixture of 15 g. of 2,4-dichlorobenzoic acid, 10 g. of p-methylphenol, 0.5 g. of copper powder and g. of anhydrous potassium carbonate in 200 ml. of dimethylformamide is heated to 165C and maintained thereat with stirring and under a nitrogen atmosphere. After monitoring via tlc'indicates the reaction is substantially complete, the reaction mixture is diluted with water, treated with charcoal, filtered and the clear filtrate acidified. The precipitate is'isolated by suction filtration, washed neutral and dried 'to give 2-(pmethylphenyloxy)-4-chlorobenzoic acid.

A mixture of 12 g. of 2-(p-rnethylphenyloxy)-4- chlorobenzoic acid, 72 g. of potassium permanganate, 200 ml. of t-butanol and 350 ml. of water is refluxed for 4.5 hours. After this time, the t-butanol is distilled off, and the reaction mixture is filtered. The filtrate is acidified to give 2-(p-carboxyphenyloxy)-4-chlorobenzoic acid which can be recrystallized from benxenezheptane. 1

Two g. of 2-(p-carboxyphenyloxy)-4-chlorobenzoic acid in 20 ml. of concentrated sulfuric acid is stirred at 80C for 1 hour. After this time, the reaction mixture is poured into 200 ml. of icewater and the resultant mixture is heated on a steam bath for 15 minutes. The mixture is cooled and filtered with th precipitate being washed with water and then recrystallized from acetic acid to give6-chloroxanthone-2-carboxylic acid.,

Example 2 6-Chlor0xanthone-2-carboxylic acid (2.5 g.) and 1.8

I g. of sodium methyl mercaptide in 40 ml. of hexamethylphosphoramide (HMPA) is-stirred for two hours at 100C. After acidification, the product is filtered off, washed with water and dried to give 6-(methylthio)- xanthone-Z-carboxylic acid.

In like manner, the following compounds can be prepared? 16 6-(ethylthio)-xanthone-2-carboxylic acid, 6-( n-propylthio)-xanthone-2 c arboxylic acid, 6-(isopropylthio)-xanthone 2carboxylic acid,. 6-(n-buthylthio)-xanthone 2-carboxylic acid,

- 6-(isobutylthio)-xanthone2-carboxylic acid,

I 6-(sec-butylthio)-xanthone-2-carboxylic acid, 6-(t-butylthio)-xanthone-2-carboxylic acid, 6-(pentylthio)rxanthone-2-carboxylic acid, 6-(cyclopropylthio)-xanthone-2-carboxylic acid, 6-(cyclobutylthio)-xanthone-2-carboxylic acid, and 6-(cyclopentylthio)-xanthone-2-carboxylic acid. The compound 6-methoxyxanthone-2-carboxylic acid is prepared by employing sodium methoxide in the above procedure.

Example 3 A mixture of l l g. carboxylic acid in 100 ml. of concentrated aqueous hydrogen iodine and 100 ml. of acetic acid is refluxed for 4 hours. After this time, the mixture is cooled, diluted with water, and filtered. The precipitate is washed and dried to give 6-hydroxyxanthone-Zcarbox'ylic acid.

' Example 4 i A mixture of 4 g. of 6-hydroxyxanthone-2-carb0xylic acid, 10 g. of methyl'iodid'e, and 10 g. of lithium carbonate in 50 ml. of dimethylformamide is stirred at room temperature. for a period of 16 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant mixture exra ed ith thx ,assists-.lbsszxm stsar filtst d' through alumina to give methy l 6-hydroxyxanthone-2- carboxylate which can be recrystallized from methanol.

Example 5 To a solution of 6.2 g. of methyl 6-hydroxyxanthone- 2carboxylate in 100 ml. of dimethylformamide are added I g. of sodium hydride. The mixture is stirred for 10 minutes at, room temperature under nitrogen. Dimethylthiocarbamoyl chloride (3 g.) is then added thereto and the resultant mixture stirred at C for 6 1 hours and then at room temperature for 16 hours. The mixture is then poured into 200 ml. of water containing .1 ml. of acetic acid; the resultantmixture is filtered and the solid dried to 'give methyl 6- dimethylthiocarbamoyloxyxanthone-Zcarboxylate.

Methyl '6-dimethylthiocarbamoyloxyxanthone-2- carboxylate (8 g.) in 150 ml. of sulfolane is stirred at 230C under nitrogen. After a total of 6 hours under these conditions tlc indicates the absence of starting material. The mixture is cooled to C and ml. of hot water are slowly added. The mixture is then cooled and the. filtered solid washed with water and dried to give, methyl 6- (dimethylcarbamoylthio)-xanthone-2- carboxylate.

Methyl 6-(dimethylcarbamoylthio)-xanthone-2- carboxylate (7.5 g.), 10 g. of potassium hydroxide and 250 ml. of 80% aqueous ethanol is refluxed for'l hour. After this time, 250 ml. of water are added and the mixture is treated with charcoal, filtered, acidified. The product isfiltered off and dried to give 6- mercaptoxanthone-2-carboxylic acid.

Example 6 of 6-methoxyxanthone-2- g. of 6-mercaptoxanthone-2- stirred for 16 hours at 60C. The mixture is then poured into dilute hydrochloric acid and the resultant mixture extracted with ethyl acetate. The extracts are chromatographed on alumina (methylene chloride) to give methyl 6(me'thylthio)-xanthone-2-carboxylate (i.e. methyl 6-thiomethoxyxanthone-Z-carboxylate) which can be recrystallized from methylene chloridezmethanol.

A mixture of 580 mg. of methyl 6-(methylthio)- xanthone-Z-carboxylate, 30 ml. of ethanol, ml. of saturated sodium carbonate solution and 5 ml. of water is refluxed for 1 hour. The mixture is then cooled, acidified and the precipitate filtered off to give 6- (methylthio)-xanthone-2-carboxylic acid (i.e. 6- thiomethoxyxanthone-2-carboxylic acid) as also prepared in the alternative method described in Example 2.

A mixture of 0.8 g. of 6-mercaptoxanthone-2- carboxylic acid, 2 ml. of 2-bromopropane, and excess potassium carbonate in 50 ml. of dimethylformamide is stirred for 24 hours at 75C. Dilute hydrochloric acid and ethanol are added, the solid filtered off and washed. The solid is saponified with sodium carbonate in aqueous methanol minutes reflux). The alkaline solution is diluted with water, treated with charcoal, filtered, and acidified to give 6-(isopropylthio)-xanthone- 2-carboxylic acid which can be recrystallized from tetrahydrofuramethyl acetate.

In a similar manner (and alternative to the method of Example 2), the following are prepared from the respective starting compounds:

6-(ethylthio)-xanthone-2-carboxylic acid,

6-(n-propylthio)-xanthone-2-carboxylic acid, 6-(n-butylthio)-xanthone-2-carboxylic acid, 6-(sec-butylthio)-xanthone-2-carboxylic acid, 6-(isobutylthio)-xanthone-2-carboxylic acid, 6-(t-butylthio)-xanthone-2-carboxylic acid, 6-(n-pentylthio)-xanthone-2-carboxylic acid, -(cyclopropylthio)-xanthone-2-carboxylic acid, 6-(cyclobutylthio)-xanthone-2-carboxylic acid, and 6-(cyclopentylthio)-xanthone-2-carboxylic acid.

Example 7 Methyl 6-(methylthio)-xanthone-2-carboxylate (764 mg), 2 m1. of hydrogen peroxide (30%), and 40 ml. of acetic acid are heated on the steam bath (80C) for 90 minutes. Tlc indicates the absence of starting material. The mixture is diluted with 60 ml. of hot water, and the mixture is cooled, the solid is filtered off and dried to give methyl 6-methylsulfonylxanthone-2-carboxylate which can be recrystallized from acetic acidzwater.

Methyl 6-methylsulfonylxanthone-2-carboxylate (660 mg), 1 g. of potassium hydroxide, and 60 ml. of 80% aqueous ethanol are refluxed for 30 minutes. The mixture is filtered, acidified, and the solid filtered off to give 6-methylsulfonylxanthone-2-carboxylic acid.

Likewise, from the respective starting compounds are prepared the following compounds:

6-isopropylsulfonylxanthone-2-carboxylic acid,

6-ethylsulfonylxanthone-2-carboxylic acid, 6-n-propylsulfonylxanthone-Z-carboxylic acid, 6-n-butylsulfonylxanthone-Z-carboxylic acid, 6-sec-butylsulfonylxanthone-Zcarboxylic acid, 6-isobutylsulfonylxanthone-2-carboxylic acid, 6-t-butylsulfonylxanthone-Z-carboxylic acid, 6-n-pentylsulfonylxanthone-Z-carboxylic acid,

l8 o-cyclopropylsulfonylxanthone-Z-carboxylic acid, 6-cyclobutylsulfonylxanthone-Z-carboxylic acid, and o-cyclopentylsulfonylxanthone-2-carboxylic acid.

Example 8 Methyl 6-(methylthio)-xanthone-2-carboxylate (927 mg.) in ml. of methylene chloride is cooled to 0C (ice). m-Chloroperbenzoic acid (555 mg.) is then added and the mixture is stirred at 0C for 75 minutes. The reaction mixture is then filtered through alumina and the column washed with methylene chloride to give methyl 6-methylsulfinylxanthone-2-carboxylate which can be recrystallized from benzenezheptane.

Methyl 6-methylsulfinylxanthone-2-carboxylate (720 mg. 75 ml. of ethanol, and 10 ml. of 5% of sodium hydroxide are refluxed for 30 minutes. The mixture is cooled, partially evaporated and acidified. The precipitate is filtered off, washed and dried to give 6methylsulfinylxanthone-2-carboxylic acid which can be recrystallized from acetic acid.

Likewise, from the respective starting compounds are prepared the following compounds:

6-isopropylsulfinylxanthone-Z-carboxylic acid,

6-ethylsulfinylxanthone-2-carboxylic acid, 6-n-propylsuIfinylxanthone-2-carboxylic acid, o-n-butylsulfinylxanthone-2-carboxylic acid, 6-sec-butylsulfinylxanthone-2-carboxylic acid, 6-isobutylsulfinylxanthone-2-carboxylic acid, 6-t-butylsulfinylxanthone-2-carboxylic acid, 6-n-pentylsulfinylxanthone-2-carboxylic acid, o-cyclopropylsulfinylxanthone-2 carboxylic acid, 6-cyclobutylsulfinylxanthone-Z-carboxylic acid, and 6-cyclopentylsulfinylxanthone-Z-carboxylic acid.

The procedures of Examples 7 and 8 can be practiced upon the corresponding acid starting compounds .to give the same products without the need of the hydrolysis step.

Example 9 One g. of 6-mercaptoxanthone-2-carboxylic acid is dissolved in 30 ml. of acetic acid containing 3 ml. of concentrated hydrochloric acid under warming. The solution is then saturated with chlorine gas and stirred at room temperature overnight. The solution is then diluted with water and the precipitate filtered off, washed, and dried to give o-chlorosulfonylxanthone-2- carboxylic acid.

The thus-prepared chlorosulfonyl compound is then treated with aqueous potassium hydroxide to give 6-sulfoxanthone-Z-carboxylic acid.

Example 10 A mixture of l g. of 6-chlorosulfonylxanthone-Z- carboxylic acid, 2 ml. of concentrated aqueous ammonia, and 20 ml. of dioxane is stirred at room temperature overnight. The mixture is then diluted with water,

, acidified and the solid filtered off and dried to give 6- 6-n-propylsulfamoylxanthone-2carboxylic acid,

o-isopropylsulfamoylxanthone-2-carboxylic acid,

6-dimethylsulfamoylxanthone-2-carboxylic acid,

6-diethylsulfamoylxanthone-2-carboxylic acid,

o-di-n-propylsulfamoylxanthone-2-carboxylic acid,

6-di-isopropylsulfamoylxanthone-Z-carboxylic acid,

and so forth.

Example 1 l l,3-Dicarbomethoxy-4-bromobenzene and mmethylthiophenol are condensed by the procedure of Example 1, paragraph 1, to give l,3-dicarbomethoxy- 4-(m-methylthiophenyloxy)-benzene. This compound is hydrolyzed with a 5% potassium hydorxidezmethanol solution at reflux for 1 hour to give l,3-dicarboxy-4- (m-methylthiophenyloxy)-benzene. The resultant compound is cyclized according to the procedure of Example 1, paragraph 3, to give 6-(methylthio)-xanthone-2- carboxylic acid.

In like manner, the other 6-(lower alkylthio)- xanthone-Z-carboxylic acids and 6-chloroxanthone-2- carboxylic acid are prepared from the appropriate starting compounds.

The thus-prepared compounds are useful as described above in Examples 2, 7, and 8.

Example l2 6-Lower alkylxanthone-2-carboxylic compounds are prepared in accordance with the procedures of Example l I from m-lower alkylphenol starting compounds. Thus prepared, for example, are:

6-ethylxanthone2-carboxylic acid, -n-propylxanthone-Z-carboxylic acid, o-n-butylxanthone-2-carboxylic acid, 6-isobutylxanthone-Z-carboxylic acid, 6-n-pentylxanthone-2-carboxylic acid, 6-isopentylxanthone-2-carboxylic acid, 6-sec-pentylxanthone-Z-carboxylic acid, 6-t-pentylxanthone-Z-carboxylic acid, 6-n-hexylxanthone-2-carboxylic acid, 6-cyclopropylmethylxanthone-2-carboxylic acid, 6-cycl0butylmethylxanthone-Z-carboxylic acid, and 6-cyclopentylmethylxanthone-2-carboxylic acid. The methyl esters thereof are prepared as described in Example 4.

Example 13 A mixture of 4 g. of 6-ethylxanthone-2-carboxylic acid, g. of methyl iodide, and 10 g. of potassium carbonate in 50 ml. of dimethylformamide is stirred at room temperature for a period of 16 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant mixture extracted with ethyl acetate. The extracts are filtered through alumina to give methyl 6-ethylxanthone-2- carboxylate which can be recrystallized from methanol.

A suspension of 2.5 g. of methyl 6-ethylxanthone-2- carboxylate and 2.5 g. of chromic oxide in 190 ml. of acetic acid and 10 ml. of acetic anhydride is stirred at room temperature for a period of 6 hours. After monitoring the reaction by tlc indicates the absence of starting material, 10 ml. of isopropanol are added and the resultant mixture warmed on the steam bath. Water (200 ml.) is then added portionwise to the resultant mixture which is cooled to room temperature. The precipitate is filtered off, washed, and dried to obtain methyl 6-acetylxanthone-2-carboxylatc.

A mixture of 1.09 g. of methyl 6-acetylxanthone-2- carboxylate, ml. of isopropanol, 5 ml. of saturated sodium carbonate solution, and 25 ml. of water is refluxed for 2 hours. The resultant mixture is then acidified, cooled and the crystals filtered off, washed, and dried to give 6-acetylxanthone-2-carboxylic acid.

The foregoing procedures can be followed with other 6-substituted methyl compounds (prepared according to the procedures of Example 12) to give the corresponding 6-acyl compounds, to wit:

6-propionylxanthone-2-carboxylic acid,

o-n-butyrylxanthone-2-carboxylic acid, 6-isobutyrylxanthone-2-carboxylic acid, 6-n-pentanoylxanthone-2-carboxylic acid, 6-isopentanoylxanthone-2-carboxylic acid, 6-sec-pentanoylxanthone-2-carboxylic acid, o-t-pentanoylxanthone-2-carboxylic acid, 6-n-hexanoylxanthone-Z-carboxylic acid, 6-cyclopropylcarbonylxanthone-2-carboxylic acid, 6-cyclobutylcarbonylxanthone-Z-carboxylic acid,

and 6-cyclopentylcarbonylxanthone-Z-carboxylic acid.

Example 14 A mixture of 1.077 g. of methyl 6-acetylxanthone-2- carboxylate, 200 mg. of sodium borohydride and ml. of tetrahydrofuran is stirred for 2.5 hours at room temperature. The reaction is monitored by tlc. After this period of time, a 5% aqueous acetic acid solution is added to the reaction mixture dropwise to neutrality and the resultant solution evaporated under vacuum and crystallized by the addition of ethanol and hot water. The precipitate is filtered off, washed and dried to give methyl 6-( l-hydroxyethyl)-xanthone-2- carboxylate.

A mixture of 860 mg. of methyl 6-( l-hydroxyethyl)- xanthone-Z-carboxylate, 60 ml. of ethanol and 2 ml. of 2N sodium hydroxide is refluxed for 30 minutes. The

resultant mixture is cooled, acidified and the precipitate is filtered off, washed, and dried to given 6-(lhydroxyethyl)-xanthone-2-carboxylic acid.

The foregoing procedures are practiced upon the other 6-acyl methyl esters prepared as described in Example l3 to give the following products, through their respective methyl esters:

6-( l-hydroxy-n-propyl )-xanthone-2-carboxylic acid,

6-( l-hydroxy-n-butyl )xanthone-2-carboxylic acid,

6-( l-hydroxy-isobutyl)-xanthone-2-carboxylic acid,

6-( l-hydroxy-n-pentyl)-xanthone-2-carboxylic acid,

6( l-hydroxy-isopentyl)-xanthone-2-carboxylic acid,

6-( l-hydroxy-sec-pentyl )-xanthone-2-carboxylic acid,

6-( l-hydroxy-t-pentyl)-xanthone-2-carboxylic acid,

6-( l-hydroxy-n-hexyl)-xanthone-2-carboxylic acid,

6-(( cyclopropyl)hydroxymethyl)-xanthone-2- carboxylic acid,

6-( cyclobutyl )hydroxymethyl )-xanthone-2- carboxylic acid, and

6-( cyclopentyl )hydroxymethyl )-xanthone-2- carboxylic acid.

Example 15 m-Methoxyphenol and the methyl diester of 4- bromo-l,3-dicarboxy benzene are condensed and hydrolyzed to 4-(m-methoxyphenyloxy)- l ,3- dicarboxybenzene according to the procedure of Example l. This compound is then cyclized (Example 1,

paragraph 3) to give 6-methoxyxanthone-Z-carboxylic acid which is useful as described in Example 3 et seq.

Example 16 A mixture of 51.5 g. of l,3-dimethyl-4-iodobenzene (4-iodo-m-xylene), 40 g. of m-methylthiophenol, 16 g. of cuprous oxide in 300 ml. of dimethylacetamide is heated to the boiling point and maintained under reflux 190C) for 144 hours with stirring and under a nitrogen atmosphere. The reaction mixture is then poured into ice water and extracted with ether and the extracts Example 17 A mixture of l,3-dimethyl 4-bromobenzene, 10.5 g.

of m-methoxyphenol, 4.65 g. of cuprous oxide, 40 ml. of tetramethylurea, and 75 ml. of N-methylpyrrolidone is stirred at 165 for 96 hours. The resultant mixture is diluted with water and extracted with methylene chloride. The methylene chloride extracts are chromatographed on 300 g. of alumina with gradient elution using hexanezether to give l,3-dimethyl-4-(m-methoxyphenyloxy) benzene.

A mixture of 12 g. of l,3-dimethyl-4(m-methoxyphenyloxy)-benzene, 72 g. of potassium permanganate, 200 ml. of t-butanol and 350 ml. of water is refluxed for 4 1/2 hours. After this time, the t-butanol is distilled off, and the reaction mixture is filtered. The filtrate is acidified to give l,3-dicarboxy-4-(m-methoxyphenyloxy)-benzene which can be recrystallized from benzenezheptane.

A mixture of 3 g. of l,3-dicarboxy-4-(m-methoxyphenyloxy)-benzene, 75 ml. of polyphosphoric acid, and 75 ml. of sulfolane is stirred at 125C for a period of 2 hours. After this time, the reaction mixture is poured into water, filtered and the precipitate washed. The precipitate is recrystallized from acetic acid (charcoal) to give 6-methoxy-xanthone-2-carboxylic acid which can be converted to 5-hydroxyxanthone-2- carboxylic acid.

In a similar manner, the foregoing procedure can be practiced utilizing other m-lower alkoxyphenol starting compounds to prepare the corresponding products, for example,

6-ethoxyxanthone-2-carboxylic acid,

6-n'propoxyxanthone-2-carboxylic acid,

o-isopropoxyxanthone-2-carboxylic acid,

6-n-butoxyxanthone-2-carboxylic acid, and so forth, which can each be converted to 5-hydroxyxanthone-2- carboxylic acid.

Example l8 An ice-cooled solution of 5 grams of acetanilide and 15 g. of aluminum chloride in ml. of dichloroethane I 22 is treated with 5 g. of enzoyl chloride in portions. The mixture is then heated at C for 3 hours, decomposed with ice and dilute hydrochloric acid and the resulting solid isolated by suction filtration and recrystallized from ethanol:water to give p-benzoylacetanilide.

p-Benzoylacetanilide (2.8 g.) and ml. of IN hydrochloric acid are refluxed for 6 hours. After cooling, the solution is made alkaline by the addition of 2N sodium hydroxide solution and extracted with ether to give 4-aminobenzophenone, which is recrystallized from methanol.

Bromine (5.5 g.) is added dropwise to a stirred solution of 6.75 g. of 4-aminobenzophenone' in ml. of chloroform. After the addition is complete, stirring is continued for 30 minutes. Dilute sodium bicarbonate solution is added and the mixture is extracted with chloroform. The resulting bromo derivative can be recrystallized from methanol.

4-Amino-3- bromobenzophenone (l 1.4 g.) is sus pended in ahot mixture of 10 ml. of concentrated hydrochloric acid and 10 ml. of water. After cooling the mixture to 0C, a solution of 3.0 g. of sodium nitrite in 10 ml. of water is added dropwise. To the resulting clear solution of the diazonium-chloride, a solution of 6 g. of sodium fluroborate in 10 ml. of water is added with vigorous stirring. The precipitate is isolated by suction filtration, washed successively with 5% fluroboric acid, methanol, and ether and left to dry in the air.

Acetic acid (15 ml.) is added dropwise to a cooled solution of 2.5 g. of the diazonium fluroborate in 25 ml. nickel carbonyl. The mixture is then concentrated in vacuo and diluted with water. The precipitated 4-benzoyl-2-bromobenzoic acid is collected on a sintered glass filter and recrystallized from ethanol.

The resultant compound is esterified as described in Example 4 and then reacted with methyl phydroxybenzoate as described in Example 16, first paragraph, followed by hydrolysis (Example 5, last paragraph) and cyclization (Example 1, last paragraph) to give 6-benzoylxanthone-2-carboxylic acid. The later can be reduced (Example 14, first paragraph) to give 6-( phenyl )hydroxymethyl )-xanthone-2-carboxylic acid.

In like manner, the following are prepared:

6-propionylxanthone-2-carboxylicacid;

6-n-butyrylxanthone-2-carboxylic acid; 6-isolbutyrylxanthone-2-carboxylic acid; 6-n-pentanoylxanthone-2-carboxylic acid; 6-isopentanoylxanthone-Z-carboxylic acid; 6-sec-pentanoylxanthone-Z-carboxylic acid; -t-pentanoylxanthone-2-carboxylic acid; 6-n-hexanoylxanthone-2-carboxylic acid; 6-n-heptanoylxanthone-2-carboxylic acid; 6-n-octanoylxanthone-2-carboxylic acid; o-n-nonanoylxanthone-Z-carboxylic acid; 6-cyclopropylcarbonylxanthone-2-carboxylic acid; 6-cyclobutylcarbonylxanthone-Zcarboxylic acid; 6-cyc|opentylcarbonylxanthone-Z-carboxylic acid; -cyclohexylcarbonylxanthone-Z-carboxylic acid; 6-trifluoroacetylxanthone-2-carboxylic acid; 6-difluoroacetylxanthone-Z-carboxylic acid; 6-trichloroacetylxanthone-Z-carboxylic acid; 6-dichloroacetylxanthone-Z-carboxylic acid;

6-( p-chlorobenzoyl)-xanthone-2-carboxylic acid;

6-(p-methylbenzoyl)-xanthone-2-carboxylic acid;

6-(p-methoxybenzoyl)-xanthone-2-carboxylic acid; 6-(p-thiomethoxybenzoyl)-xanthone-2-carboxylic acid;

6-furoylxanthone-2-carboxylic acid;

fi-pyrroylxanthone-2-carhoxylic acid;

6-thenoylxanthone-Z-carboxylic acid;

o'pyridylcarbonylxanthone-Z-carboxylic acid;

6-imidazolylcarbonylxanthone-2-carboxylic and o-oxazolylcarbonylxanthone-2-carboxylic acid;

and thence:

6( l-hydroxy-n-propyl)-xanthone-2-carboxylic acid;

6-( l-hydroxy-n-butyl)-xanthone-2-carboxylic acid;

6-( l-hydroxyisobutyl)-xanthone-2-carboxylic acid;

6-( l-hydroxy-n-pentyl)-xanthone-2-carboxylic acid;

6-( l-hydroxyisopentyl)-xanthone-2-carboxylic acid;

6-( l-hydroxy-sec-pentyl )-xanthone-2-carboxylic acid;

6-( l-hydroxy-t-pentyl)-xanthone-2-carboxylic acid;

6-( l-hydroxy-n-hexyl)-xanthone 2-carboxylic acid;

6-( l-hydroxy-n-heptyl)-xanthone-2-carboxylic acid;

6-( l-hydroxy-n-octyl)-xanthone-2-carboxylic acid;

6-( l-hydroxy-n-nonyl)-xanthone-2-carboxylic acid;

6-((cyclopropyl)hydroxymethyl)-xanthone-2- carboxylic acid;

6-( cyclobutyl )hydroxymethyl )-xanthone-2- carboxylic acid;

6-((cyclopentyl)hydroxymethyl)-xanthone-2- carboxylic acid;

6-(( cyclohexyl)hydroxymethyl)-xanthone-2- carboxylic acid;

6-( 2,2,2-trifluoro-1-hydroxyethyl)-xanthone-2- carboxylic acid;

6-(2,2-difluoro-1-hydroxyethyl)-xanthone-2- carboxylic acid;

6-( 2,2,2-trichlorol -hydroxyethyl )-xanthone-2- carboxylic acid;

6-( 2,2-dichlorol -hydroxyethyl )-xanthone-2- carboxylic acid;

6-( p-chlorophenyl )hydroxymethyl )-xanthone-2- carboxylic acid;

6-( (p-methylphenyl )hydroxymethyl )-xanthone-2- carboxylic acid;

6-( p-methoxyphenyl )hydroxymethyl )-xanthone-2- carboxylic acid;

6-( (p-thiomethoxyphenyl )hydroxymethyl xanthone-Z-carboxylic acid;

acid;

6-( (furyl )hydroxymethyl)-xanthone-2-carboxylic 6-?p rryl)hydroxymethyl)-xanthone-2-carboxylic 6i ftll 'lienyl)hydroxymethyl )-xanthone-2-carboxylic 6-i fpg i'idyl)hydroxymethyl)-xanthone-2-carboxylic 6-( imidazolyl )hydroxymethyl )-xanthone-2- carboxylic acid; and

6-( (oxazolyl)hydroxymethyl )-xanthone-2-carboxylic acid.

Example 19 5 Methyl 6-methylxanthone-2-carboxylate is prepared by the procedure of Example I l from m-methylphenol.

To a solution of 2.4 g. of methyl 6-methylxanthone-2- carboxylate in 30 ml. acetic acid and 30 ml. acetic anhydride are added 4.8 ml. concentrated sulfuric acid at C. After the addition of 5.6 g. of chromic acid, the mixture is stirred for hours. ,The crude diacetoxymethyl intermediate is isolated by diluting the reaction mixture with water and filtering off the precipitate.

The formyl derivative is obtained by refluxing the diacetoxymethyl compound thus obtained with 10 ml. of 2N sulfuric acid in ml. methanol for 30 minutes, cooling, diluting with 60 ml. water and filtering off the precipitate to give o-formylxanthone-Z-carboxylic acid. This compound can be reduced as described above to o-hydroxymethyl-xanthone-2-carboxylic acid.

Example 20 A mixture of 2 g. of 6-( l-hydroxyethyl)-xanthone-2- carboxylic acid in 8 ml. of pyridine and 4 ml. of acetyl' chloride is heated at steam bath temperatures for 1 hour. The mixture is then poured into HCl/ice water and the solid which forms is collected by filtration, washed with water and dried to yield 6-( l-acetoxyethyl)- xanthone-2carboxylic acid.

Upon substitution of the appropriate acyl chloride in the above procedure and, in addition, employing as starting compounds the products listed in Example 14, the following compounds are prepared:

6-( Lpropionyloxyethyl )-xanthone-2-carboxylic acid,

6-( l-butyryloxyethyl )-xanthone-2-carboxylic acid,

6'( l-pentanoyloxyethyl )-xanthone-2-carboxylic acid,

6-( l-acetoxy-n-propyl )-xanthone-2-carboxylic acid,

6-( l-propionyloxy-n-propyl)-xanthone-2-carboxylic acid, and so forth,

6-( l-acetoxy-n-butyl)-xanthone-2-carboxylic acid,

6-( l-propionyloxy-n-butyl )-xanthone-2-carboxylic acid, and so forth,

6-( l-acetoxyisobutyl)-xanthone'2-carboxylic acid,

6-( l-propionyloxyisobutyl )-xanthone-2-carboxylic acid, and so forth,

6-( (cyclopropyl )acetoxymethyU-xanthone-Z- carboxylic acid, and so forth,

6-( phenyl )acetoxymethyl )-xanthone-2-carboxylic acid, and so forth.

Example 2 I To a mixture of 2.5 g. of methyl 6-( l-hydroxyethyl)- xanthone-2-carboxylate and 500 mg. of sodium hydride in 45 ml. of dimethylformamide is added 2 ml. of methyl iodide and the mixture is stirred at room temperature for [6 hours. The mixture is then poured into dilute HCl/ice water, filtered and dried to give methyl 7-( l-methoxyethyl)-xanthone-2-carboxylate.

The resultant product is hydrolyzed according to the procedure of the last paragraph of Example 5 to give 6-( l-methoxyethyl)-xanthone-2-carboxylic acid.

Upon substitution of the appropriate alkyl or cycloalkyl iodide or bromide and, in addition, employing as starting compounds the products listed in Example 14, the following compounds are products lised in Example 14, the following compounds are prepared, through their respective esters:

6-( l-ethoxyethyl )-xanthone-2-carboxylic acid,

6-( 1-n-propoxyethy|)-xanthone-2-carboxylic acid,

6-( l-butoxyethyl)-xanthone-2-carboxylic acid,

6-( 1-n-pentyloxyethyl)-xanthone-2-carboxylic acid,

' o-(isopropoxyethyl)-xanthone-2-carboxylic acid,

6-( l-isobutoxyethyl)-xanthone-2-carboxylic acid,

6-( l-cyclopentyloxyethyl)-xanthone-2-carboxylic acid,

6-( l-cyclopropyloxyethyl )-xanthone-2-carboxylic acid, 6-( l-methoxy-n-propyl)-xanthone-2-carboxylic acid, 6-( l-methoxyl-n-butyl)-xanthone-2-carboxylic acid,

6-( l-methoxyisobutyl)-xanthone-2-carboxylic acid,

6-((cyclopropyl)methoxymethyl)-xanthone-2- carboxylic acid,

6-( (cyclopropyl )ethoxymethyl )-xanthone-2- carboxylic acid,

6-( phenyl )methoxymethyl )-xanthone-2-carboxylic acid, and

6-( phenyl )ethoxymethyl )-xanthone-2-carboxylic acid.

Example 22 A mixture of 1.6 g. of methyl 6-(l-hydroxyethyl)- xanthone-Q-carboxylate, 50 ml. of methylene chloride, 50 ml. of isobutene and 2 ml. of BF /H PO, catalyst are shaken in a pressure bottle for four days at room temperature. The reaction mixture is diluted with methylene chloride, washed with bicarbonate solution, then water, dried and evaporated and crystallized from methanol to give methyl 6-(l-t-butoxyethyl)-xanthone- 2-carboxylate.

Hydrolysis provides 6-( lt'butoxyethyl)-xanthone-2- carboxylic acid.

Likewise, the following products are prepared from the respective starting compounds:

6-( l-t-butoxy-n-propyl )-xanthone-2-carboxylic acid,

6-( l-t-butoxy-isobutyl) xanthone-2-carboxylic acid,

6-( (cyclopropyl )-t-butoxymethyl)-xanthone-2- carboxylic acid, and

6-( phenyl )-t-butoxymethyl )-xanthone-2-carboxylic acid.

Example 23 Ten milliliters of dihydropyran are added to a solution of 1 g. of methyl 6-( l-hydroxyethyl)-xanthone-2- carboxylate in 50 ml. of benzene. About 1 ml. is removed by distillation to remove moisture and 0.4 g. of p-toluenesulfonic acid is added to the cooled solution. This mixture is allowed to stand at room temperature for four days, and is then washed with aqueous sodium carbonate solution and water, dried and evaporated. The residue is crystallized from chloroform/methanol/- pyridine to yield methyl 6-( l-tetrahydropyran-2- yloxyethyl)-xanthone-2-carboxylate.

Hydrolysis provides yloxyethyl)-xanthone-2-carboxylic acid. I

By use of dihydrofuran in the above procedure, 6-( ltetrahydrofuran-Z '-yloxyethyl )-xanthone-2-carboxylic acid is prepared.

In like manner, the following compounds are prepared:

6-( l-tetrahydropyranf2-yloxy-n-propyl )-xanthone- 2-carboxylic acid,

6-( l-tetrahydropyran-2'-yloxy-isobutyl)-xanthone-2- carboxylic acid,

6-( l-tetrahydropyran-2 '-yloxy-n-butyl )-xanthone-2- carboxylic acid, and the tetrahydrofuran-2-yloxy compounds corresponding thereto.

3.5 Grams of methyl 6-( l-hydroxyethyl)-xanthone-2- carboxylate in l5O ml. of benzene and 500 mg. of p-toluene-sulfonic acid (dried by azeotropic distillation from benzene) are mixed'together and the reaction mixture is treated with 4-methoxy-5,6-dihydro-2H- pyran, 1 ml. at a time until reaction is complete (followed by tlc). The reaction is quenched by addition of one-half ml. of triethylamine, washed with water, and crystallized with care from methanol containing pyridine to give methyl 6-(l-4-methoxytetrahydropyranv4-yloxyethyl)-xanthone-2-carboxylate. I

6-( l-tetrahydropyran-2'- Hydrolysis provides 6-( l-4- methoxytetrahydropyran-4-yloxyethyl)-xanthone-2- carboxylic acid.

A solution of 1.4 g. of aluminum chloride in 25 ml. of tetrahydrofuran is treated with a solution of 0.4 g. of lighium aluminum hydride in 100 ml. of ether. Methyl 6-( l-4'-methoxytetrahydropyran-4'-yloxyethyl xanthone-2-carboxylate (500 mg.) is extracted into the solution. After reduction is complete (monitored by tlc), saturated sodium chloride is added until a precipitate forms. This is filtered and the crude product is oxidized in acetic acid using excess sodium dichromate to give 6-( l-tetrahydropyran-4'-yloxyethyl )-xanthone-2- carboxylic acid.

In like manner, the following compounds are prepared:

6-( l-4-methoxytetrahydropyran-4' yloxy-n-propyl xanthone-Z-carboxylic acid,

6-( l-tetrahydropyran-4'-yloxy-n-propyl)-xanthone- 2-carboxylic acid,

6-( 1-4-ethoxytetrahydropyran-4-yloxyethyl)- xanthone-Z-carboxylic acid,

6-( 1-4-methoxytetrahydropyran-4-yloxyisobutyl xanthone-2-carboxylic acid, and

6-( l-4-propoxytetrahydropyran-4'-yloxy-n-propyl xanthone-2-carboxylic acid.

Example 24 A mixture of 4.5 grams of 6-methylsulfinylxanthone- 2-carboxylic acid, 10 g. of methyl iodide, and 10 g. of lithium carbonate in ml. of dimethylformamide is stirred at room temperature for a period of 18 hours. After this period of time, the reaction mixture is poured into dilute hydrochloric acid-ice and the resultant precipitate is filtered off and washed to give methyl 6- methylsulfinylxanthone-2-carboxylate.

The foregoing procedure is repeated using the alternate lower alkyl iodides so as to prepare the corresponding lower alkyl acid esters hereof, e.g.

ethyl 6-methylsulfinylxanthone-2-carboxylate,

n-propyl 6-methylsulfinylxanthone-2-carboxylate,

isopropyl 6-methylsulfinylxanthone-Z-carboxylate, n-propyl 6-methysulfinylxanthone-Z-carboxylates, isobutyl 6-methylsulfinylxanthone-Z-carboxylate, sec-butyl -methylsulfinylxanthone-Z-carboxylate, t-butyl 6-methylsulfinylxanthone-2-carboxylate, n-pentyl 6-methylsulfinylxanthone-2-carboxylate, and so forth.

In like manner, the other xanthone-2-carboxylic acids hereof containing substituents at the C-6 position, prepared as described above, can be converted to the corresponding acid esters, e.g. methyl 6- methylsulfonylxanthone-2-carboxylate, ethyl 6- methylsulfonylxanthone-2-carboxylic acid, n-propyl 6-sulfamoylxanthone-2-carboxylic acid, and so forth.

ln the sulfo series, the esters are prepared by treating the acid with the appropriate lower alkanol under reflux and in the absence of acid to give, e.g. methyl 6-sulfoxanthone-Z-carboxylic acid and ethyl 6-sulfoxanthone-2-carboxylic acid.

Example 25 To a solution of 10 g. of o-methylsulfinylxanthone-2- carboxylic acid in 200 ml. of ethanol is added the theoretical amount of sodium hydroxide dissolved in 200 ml. of ethanol. The reaction mixture is then concentrated in vacuum to give sodium 6- methylsulfmylxanthone-Z-carboxylate.

In a similar manner, the potassium and lithium salts are prepared. Similarly, by replacing the sodium salt by means of an appropriate metal salt reagent, e.g. calcium chloride, manganese chloride, and so forth, the other xathone-Z-carboxylic acid salts are prepared, e.g.

magnesium 6-methylsulfinylxanthone-2-carboxylate,

calcium 6-methylsulflnylxanthdne-Z-carboxylate,

aluminum 6-methylsulfinylxanthone-Z-carboxylate,

ferrous 6-methylsulfinylxanthone-2-carboxylate,

zinc -methylsulfinylxanthone-2-carboxylate,

manganese 6-methylsulfinylxanthone-2-carboxylate,

ferric 6-methylsulfinylxanthone-Z-carboxylate, and

so forth.

In a similar manner, the xanthone-Z-carboxylic acid salts of the other C-6 substituted xanthone-2- carboxylic acids hereof are prepared, e.g. potassium 6-methylsulfonylxanthone-2-carboxylate, sodium 6- sulfamoylxanthone-2-carboxylate, and so forth.

In the sulfo series, use of one equivalent of base provides the sulfo acid salt and use of two or more equivalents provides the disalt, e.g. 6-sulfoxanthone-2- carboxylic acid disodium salt.

Example 26 To a mixture of 50 ml. of concentrated aqueousi ammonia in 500 ml. of methanol there are added 20 g.. of 6-sulfamoylxanthone-Z-citrboxylic acid. The resultant mixture is stirred for two hours and is then evaporated isl sir thqemmqt iutaialt 9 19-. suTfanioylxafithone-2-carboxylic acid. p A solution of g. of 6-sulfamoylxanthone-2-carboxylic acid in 50 ml. of thionyl chloride is heated at reflux for 1 hour. Thereafter, the solution is evaporated to dryness to give the corresponding acid chloride to which is added a concentrated ethereal ammonia solution. The resultant solution is evaporated giving the 6-sulfamoylxanthone- 2-carboxylic acid amide.

In like manner, the lower alkyl amides can be prepared using monoalkylamine or dialkylamine in lieu of ammonia in the above procedures. Thus prepared, e.g. are:

6-methylsulfamoylxanthone-Z-carboxylic acid amide,

N-methyl 6-n-propylsulfinylxanthone-Z-carboxylic acid amide,

N,N-dimethyl 6-dimethylsulfamoylxanthone-2- carboxylic acid amide,

N,N-diethyl 6-ethylsulfonylxanthone-2-carboxylic acid amide,

N-ethyl 6-sulfoxanthone-2-carboxylic acid amide,

N-n-propyl 6-propylsulfinylxanthone-2-carboxylic acid amide, and so forth.

Example 27 carboxylic acid, the caffeine salt of 6- propylsulfinylxanthone-Z-carboxylic acid, the lysine salt of 6-di-t-butylsulfamoylxanthone-2-carboxylic acid, the procaine salt'of 6-sec-butylsulfinylxanthone- 2-carboxylic acid, and the arginine salt of 6-sulfoxanthone-2-carboxylic acid.

Example 28 The following procedures illustrate the method by which the pharmaceutical compositions of the compounds hereof are prepared.

Sodium chloride (0.44 g.) is dissolved in ml. of a (9.47 g/l. water) sodium hydrogen phosphate solution. A sodium dihydrogen phosphate (8.00 g/l. water) solution (20 ml.) is then added thereto. The resultant solution having a pH of 7.38 is sterilized in an autoclave. This vehicle is then added to solid, dry 6- methylsulfinylxanthone-2-carboxylic acid to give a preparation suitable for intravenous injection containing 2.5 mg. of 6-methylsulfinylxanthone-2-carboxylic acid per ml. of total composition.

Example 29 The following procedure illustrates a test procedure for the compounds hereof.

Normal female (Sprague-Dawley) rats of 150 to 200 grams each are passively sensitized intradermally by injection of rat anti-egg albumin reaginic sera. After 24 hours, each rat is challenged intravenously with 1 ml. of 0.5% Evans blue, 1 mg. egg albumin plus 0.20 mg. of 6-methylsulfinylxanthone-2-carboxylic acid. Control rats receive no 6-methylsulfinylxanthone-2-carboxylic acid. The dermal bluing is recorded 15 to 25 minutes later. The rats which receive the 6- methylsulfinylxanthoner2-carboxylic acid exhibit a percent inhibition of allergic reaction whereas the control rats exhibit no inhibition.

The above procedure is repeated using 6- methylsulfonylxanthone-2-carboxylic acid, with similar results. The above procedure is repeated using oral administration, with similar results.

The C6 substituted xanthone-2-carboxylic acid compounds are administered by gavage at a dose of 5 mg. per animal 15 minutes prior to challenge. Twenty to thirty minutes after challenge the degree of dermal bluing is read, with similar results.

lnhibition of reaginic antigen-antibody reactions in rats is regarded as representative of inhibition of human reaginic antigen-antibody reactions which occur during allergic episodes.

Subjects challenged by antigen inhalation are measured for the extent of provoked degree of asthma condition by changes in airway resistance on expiration. The subject compounds are administered as an aerosol by inhalation before antigen challenge. Prevention of asthmatic conditions upon the administration of the compounds is evidenced by a decrease in airway resistance and other, subjective improvements, e.g. reduced cough.

What is claimed is:

l. A compound selected from those represented by the following formula:

lower alkyl, lower alkoxy, or lower alkylthio.

2. The compound according to claim 1 wherein R is methyl; 6-acetylxanthone-2-carboxylic acid.

3. The compound according to claim 1 wherein R is cyclopropyl; 6-cyclopropylcarbonylxanthone-2- carboxylic acid.

4. The sodium salts of the compounds according to I claim 1. 

2. The compound according to claim 1 wherein R2 is methyl; 6-acetylxanthone-2-carboxylic acid.
 3. The compound according to claim 1 wherein R2 is cyclopropyl; 6-cyclopropylcarbonylxanthone-2-carboxylic acid.
 4. The sodium salts of the compounds according to claim
 1. 